Project: Novel individualized therapies in JAK/STAT driven T-cell malignancies

Acronym	JAKSTAT-TARGET (Reference Number: ERAPERMED2018-066)
Duration	01/03/2019 - 28/02/2022
Project Topic	Mature T-cell leukemias/lymphomas (MaTCL) are hematologic malignancies of mostly incurable prospects in light of limited efficient therapies. As a heterogeneous group of tumors, single MaTCL types are rare, which impedes large-volume biomaterial and data collections and clinical studies. Hyperactivating somatic mutations in JAK/STAT genes stand out as high-incidence aberrations across MaTCL entities. Particularly the model diseases investigated here, T-cell prolymphocytic leukemia (T-PLL) and T-cell large granular lymphocyte leukemia (T-LGLL), carry those in 50-70% of cases. This interdisciplinary JAKSTAT-TARGET consortium of immunologists, hematologists, structural chemists, and systems biologists capitalizes on unique resources such as clinical registry-linked sample repositories, new high-fidelity mouse models, pipelines of structure-based target design, and in-silico machine learning tools. We propose that targeting the JAK/STAT signalling network in synergistic combinations with drugs inhibiting inter-connected other key driver pathways will improve individualized anti-leukemic efficacy. We will achieve this by three objectives (O): O1 will address the causal T-cell receptor and cytokine mediated impact on genome integrity and on the occurrence of JAK/STAT mutations. It interrogates the biochemical and functional consequences of the mutated and unmutated clones, and derives actionable differential vulnerabilities. O2 will study the performance of identified synergistic drug combinations using in-house developed optimized STAT-inhibitors in novel animal models and primary samples. O3 will implement drug-screen data from patient material into an ongoing clinical trial. Ultimately, with machine-learning algorithms we will integrate the harmonized data of genomic profiles, drug-sensitivity patterns, and clinical outcomes from all objectives toward multi-omics guided predic-tions of optimal choices for trial designs and individual-patient based therapy selection.
Network	ERA PerMed
Call	1st Joint Transnational Call for Proposals (2018)

Project partner

Number	Name	Role	Country
1	University of Helsinki	Coordinator	Finland
2	University of Cologne	Partner	Germany
3	University of Veterinary Medicine	Partner	Austria
4	University of Toronto Mississauga	Partner	Canada
5	University of Helsinki	Partner	Finland
6	University Health Network (Toronto)	Partner	Canada